By using this strategy we have identified that maintenance of oxidative-nonoxidative pentose phosphate pathways unbalance is critical for angiogenesis and cancer cell survival and vulnerable to chemotherapeutic intervention. Moreover, we have used Metabolic Control Analysis (MCA) to design combined target strategies, which have been validated by using specific inhibitors. This strategy results of great interest for the study of other multifactorial diseases. In particular, its application to achieve a better understanding of glucose metabolic network and respiratory chain to design interventions at a metabolic level in chronic obstructive pulmonary disease (COPD), has permitted us to identify bistability inherent to complex III operation which explain high ROS production in hypoxia-reoxygenation processes.
We concluded that a fully understanding of the metabolic adaptation accompanying multifactorial diseases as cancer or COPD open new ways to develop novel multi-hit therapies which works on attacking several pathways simultaneously.
This work was supported by funds of Spanish Government and European Union FEDER SAF2008-00164; ISCIII-RTICC (RD06/0020/0046); European Comission BIOBRIDGE (LSHG-CT-2006- 03793-FP6,DIAPREPP (FP7-202013) and ETEHRPATHS (FP7-222639); and Generalitat de Catalunya (2005SGR00204 and 2009SGR-1308).